Lapatinib and Trastuzumab With or Without Endocrine Therapy

The neoadjuvant setting is especially attractive for studies of predictive biologic
correlates for several reasons including early assessment of response to therapy, access to
the primary tumor, and reduced patient numbers compared to those required in the adjuvant
setting. Response to neoadjuvant therapy is a validated surrogate marker for improved
survival; it may be used to test the overall efficacy of neoadjuvant treatment regimens and
response in the primary tumor mirrors the effect of therapy on micrometastases.

Trastuzumab is an efficacious agent in HER2 overexpressing breast cancers. Our results with
neoadjuvant trastuzumab indicate that its efficacy may be better in patients with
treatment-naïve tumors compared to metastatic disease, with 26% of patients showing a partial
response after only 3 weeks of therapy. No patients progressed during this 3-week period. We
have also conducted a neoadjuvant lapatinib study given as a single agent for 6 weeks. The
response rates in this second study have been impressive with greater than 80% responses in
patients with HER2 positive locally advanced breast cancers. It is likely that the true
response rate to HER2 blockade would be higher had therapy been continued for longer. We
therefore hypothesize that lapatinib, a dual tyrosine kinase inhibitor, together with
trastuzumab, will result in tumor regression when given as neoadjuvant therapy in HER2
overexpressing breast cancer. We will compare lapatinib plus trastuzumab for 12 weeks, and if
the tumors express ER, estrogen deprivation will also be administered.

This is a phase II trial. Clinical efficacy will be assessed by bidimensional tumor
measurements of the primary cancer at baseline, and at the end of week 12. Objective tumor
response rate defined as objective bidimensional tumor measurements after neoadjuvant
treatment at 12 weeks will be calculated, and assessed according to standard RECIST criteria.
Pathologic responses will be graded as pathologic complete response if there is no invasive
cancer in the residual breast at the time of surgery. Near pathologic complete response will
also be documented as residual disease of less than 1 cm.

Inclusion Criteria:

- All patients must be female.

- Signed informed consent.

- Locally advanced breast cancers or primary breast cancers are eligible. Locally
advanced cancers must be of clinical and/or radiologic size >3 cm, or >2 cm with
clinical evidence of axillary nodal involvement. (If tumors are less than 3 cm, we
will use radiologically measured tumor size to determine the minimal tumor size for
eligibility and in assessing tumor size during follow-up).

- HER2 overexpressing tumors defined as HercepTest score of 3+, or > 10% cells
moderately or strongly HER2 positive by other methods, or Allred semi-quantitative
score of >5, or gene amplified.

- Negative serum pregnancy test (HCG) within 7 days of starting study, if of
child-bearing potential.

- Kidney and liver function tests - all within 1.5 times the institution's upper limit
of normal.

- Performance status (WHO scale) less than 2 and life expectancy more than 6 months.

- Age at least 18 years.

- No brain or leptomeningeal disease.

- No previous or current malignancies at other sites within the last 5 years, with
exception of adequately treated cone-biopsied in situ carcinoma of the cervix uteri
and basal or squamous cell carcinoma of the skin.

Note: The presence of pathological involvement of axillary nodes will be assessed and
agreed upon by two investigators.

Exclusion Criteria:

- Pregnancy or unwillingness to use a reliable contraceptive method in women of
child-bearing potential.

- Severe underlying chronic illness or disease.

- Cardiomyopathy or baseline LVEF less than 50%.

- Other investigational drugs while on study.

- Severe or uncontrolled hypertension, history of congestive heart failure or severe
coronary arterial disease.

- Malabsorption syndrome, disease significantly affecting gastrointestinal function, or
resection of the stomach or small bowel. Subjects with ulcerative colitis are also
excluded

- Taking any lapatinib-prohibited medication within 7 days of first dose of study
medications. (See Prohibited Medications List in protocol.)